1. Field of the Invention
The invention relates to a device for the picture-providing diagnosis of tissue with the selective application of a picture-providing white light diagnosis mode and a picture-providing auto-fluorescence mode, the device having a light source whose light is led to the tissue by an endoscope, and a picture transmission unit arranged in the endoscope which transmits the picture of the tissue to a colour camera, wherein the colour camera comprises three sensors for the three colour regions red, green and blue which in each case are in connection with a picture processor unit which provides a monitor with the picture signals.
2. Description of the Prior Art
The best chance of healing cancerous lesions is to treat the lesions in the pre-malignant and early-malignant stages of the diseased lesions. The prospects for success with a curative treatment decreases when the lesion reaches the invasive carcinoma stage. Therefore the diagnosis of pre-malignant or early-malignant tissue is of significant importance.
The process of carcinogenesis from the early stage cell types up to the invasive carcinoma stage extends a time-period of several years. This pre-malignant and early-malignant phase therefore offers a large window for diagnosis in which there is given a successful treatment of the patient and tumour-prevention. Unfortunately this time frame until now for therapeutic purposes could only be insufficiently exploited which is reflected is the small five-year survival rate with patients with a bronchial carcinoma which has remained unchanged for decades. This survival rate as always lies only between 10% and 15%.
The reason why these exploitation possibilities in the given long time frame have not been sufficient up to now lies in the fact that the sensitivity of the conventional diagnosis forms—including white light endoscopy—is very small for pre-malignant and early-malignant lesions. Accordingly, many lesions remain undetected using the conventional diagnosis forms.
During the examination of a patient in the bronchial region it is desirable for the physician carrying out the examination to carry out a usual white light diagnosis to obtain an overview of the bronchial region and set up a reference diagnosis. During the examination, the physician searches for inflamed and malignant tissue such as, for example, exophytic tumours, and also for early-malignant tissue inasmuch as this is visible under white light.
With the conventional white light diagnosis, it is difficult to differentiate premalignant and early-malignant tissue from benign tissue which is why it may remain undetected. The white light diagnosis for this has an insufficient sensitivity. Accordingly the necessity of a life-saving or at least significantly life-lengthening therapy may not be recognized. The picture-providing autofluorescence diagnosis represents a decisive advantage over white light diagnosis. Autofluorescence diagnosis considerably improves the visibility or the possibility of differentiating pre-malignant and early-malignant tissue with respect to healthy, inflammed or merely metaplastically changed tissue.
Using picture-providing autofluorescence diagnosis for the diagnosis of pre-malignant or early-malignant lesions, one may ascertain that the healthy tissue differs from diseased tissue in (1) fluorescence intensity integrally over the whole emission range, i.e. in the brightness, and (2) fluorescence colour (the integral colour impression created with the observer, caused by a changing weighting of the spectral components in the fluorescence light emitted by the tissue).
With regard to the dependency of the fluorescence intensity on the condition of the tissue, FIG. 1 is referred to. Here by way of example for an excitation wavelength of 405 nm the spectral intensity Is over the wavelength W in nanometers is shown for various tissue conditions (Healthy tissue; metaplastic/inflamed, i.e., non-malignant and therefore tissue types which are not to be graded as malignant; dyplasia/CIS carcinoma in situ; and invasive). From FIG. 1 it is evident that with an increasing degree of tissue atypia or with an increasing degree of malignancy of the integral of intensity reduces.
The dependency of the fluorescence colour on the tissue condition, i.e. of the integral colour impression created with the observer, is evident from representation according to FIG. 2. Curves of the spectral fluorescence intensities Is standardized to the first fluorescence maximum are shown for the same sample as in FIG. 1 (the first fluorescence maximum occurs in the green spectral region at approximately 500 nm). The difference to the representation according to FIG. 1 lies merely in the standardization to the highlighting of the colour shifting. The curves for the different condition are however as such identical to those of FIG. 1.
As evidenced by the curves in FIG. 2, tissue having an increasing degree of tissue atypia or with an increasing degree of malignancy has an increased portion of red fluorescence (wavelengths between about 600 nm and 700 nm) relative to green fluorescence (wavelengths smaller than about 570 nm). Therefore, the tissue with an increasing degree of tissue atypia or with an increasing degree of malignancy appears reddish to an increasing amount to the observer.
An evaluation of only the brightness, i.e., the fluorescence intensity, for differentiation of tissue and thus for the diagnosis of pre-malignant and early-malignant lesions (and not evaluating the fluorescence colour) is burdened with problems because a drop of the total fluorescence intensity is not exclusively caused by tissue atypia. The drop in intensity may also be caused on account of tissue morphology. For example microscopically heavily structured but healthy tissue as well as macroscopic surface unevenness, such as possible folds in the tissue with healthy tissue, with regard to the fluorescence excitation light and also with regard to emission of fluorescence light act as “light traps” and by way of this reduce the fluorescence light detectable by the eye or the camera. Thus this type of tissue exhibits a lower intensity similar to diseased tissue.
The evaluation of tissue for pre-malignant and early-malignant lesions alone on the basis of fluorescence intensity alone may therefore lead increasingly to results which are wrongly positive and thus lead to a reduced specifity. Under this aspect with the picture-providing autofluorescence for locating pre-malignant or early-malignant lesions the colour of the tissue dependent on the tissue condition or degree of malignancy and the colour impression thus given to the observer play a decisive role. A picture-providing fluorescence diagnosis system should therefore be designed such that the colour dependent on the tissue atypia, i.e. the change in the weighting of the spectral fluorescence part share, is indeed also made visible to the observer.
FIG. 1 shows that the integral fluorescence intensity of early-malignant and malignant tissue is close to integral fluorescence intensity of healthy tissue. In combination with the finite or limited dynamics of conventional colour cameras and also of the human eye the colour shifting with respect to healthy tissue under certain circumstances may hardly be perceived or not be perceived at all. The suspected location may appear to be only darker. Similarly, colour as well as colour shiftings are to be recognized only in a limited manner. The increased brightness of the healthy tissue surrounding the suspect location acts in an irradiated manner such that colour changes, particularly with smaller suspect locations, may also not be perceived.
The difference between the fluorescence intensity of pre-malignant and early-malignant tissue (see FIG. 1) which is heavily reduced relative to the fluorescence intensity of healthy tissue may be hidden by the fact that the signals produced by the camera in these tissue regions may already be superimposed by a comparatively great noise.
From this there results problems which may be comparable with those which have already been described above.
Early-malignant and malignant lesions on account of their greatly reduced fluorescence intensity and therefore their colour shifting which is hardly perceivable may hardly be differentiated from that healthy tissue which acts in a light-swallowing' manner due to changed surface structures and which therefore may supply the observer with less fluorescence intensity than normal structured healthy tissue.
The difficulties in assessing such tissue renders obligatory the taking of a sample, in order to detect where possible all potential early-malignant or malignant sources. This reduces the false-positive rate, i.e., the specifity. However, the sample taking incurs additional time and costs. Moreover, additional biopsies necessitated by the samples likewise create additional costs. Furthermore each taking of a sample may lead to bleeding which inhibits further examination.
For including an evaluation of colour shifting into the tissue differentiation under the given circumstances it is a disadvantage that with an increasing degree of malignancy or with an increasing atypia of the tissue not only does the fluorescence intensity in the green spectral region decline but also the fluorescence intensity in the red spectral region—even if less marked (see FIG. 1). From a comprehensive point of view it would however be advantageous when the detected red light with respect to the tissue condition remains unchanged, i.e. remains constant. Furthermore, the red part share led to the observer should ideally be so high that it is clearly dominated by green fluorescence of the healthy tissue so that the healthy tissue appears green to the user, but that this red part share of the fluorescence signal significantly exceeds the signals deriving from the green fluorescence of the diseased tissue, which are smaller that those which come from healthy tissue by a factor of 10 (see FIG. 1), so that the diseased tissue appears red to the observer.
A red part share of the fluorescence signal that is independent of the condition of the tissue would lead to an improvement of the colour contrast between healthy and diseased tissue and thus to an increase of the sensitivity, caused by a significantly improved colour shifting towards the red with diseased tissue with respect to the healthy tissue, and the weakly fluorescing diseased tissue can appear brighter, caused by the then higher red part share. Furthermore a better differentiation of the diseased tissue from that healthy tissue which on account of a microscopically or macroscopically greater structured surface nature swallows light and thus appears darker than “smooth” healthy tissue would be possible. The latter tissue appears dark and the early-malignant and malignant tissue in contrast appears red.
The red fluorescence according to FIG. 1 recedes with an increasing tissue change just as the green fluorescence recedes—even if less pronounced, and the red fluorescence does not have a non-negligible dependency on the degree of tissue atypia. Accordingly, the provision of a red part share independent of the tissue condition may only be effected via an irradiation of the tissue with additional red light (besides the fluorescence excitation light). The red light remitted by way of this from the tissue is in contrast to the red fluorescence largely independent on the degree of tissue atypia. At the same time however one must ensure that the signal differences caused by the red fluorescence with different tissue conditions are eliminated or at least are almost without significance with respect to the signal in the red channel produced by the red emission.
U.S. Pat. No. 5,590,660 discloses a diagnosis system with which red light provided by a light source and then remitted at the tissue is used for tissue assessment, and specifically additionally to the fluorescence light emitted by the tissue. The system and the light source are designed so that an improved colour differentiation and thus an improved sensitivity of pre-malignant and early-malignant tissue is achieved relative to a device without adding red light with a light source. The colour impression and thus the tissue condition are only evaluated on the basis of the autofluorescence of the tissue. However, a detection unit having two cameras must be applied, in front of whose sensors there are mounted optical band-width filters which represent specially manufactured products in that they do not correspond to the filter specifications of conventional 3-chip cameras suitable for white light endoscopy. The idea on which U.S. Pat. No. 5,590,660 is based is specifically that the whole detected wavelength region is divided up into two separate spectral regions: a first wavelength region in which essentially the whole autofluorescence light lies (wavelengths between 500 nm and 650 nm; according to the sensitivity of the sensors used here the autofluorescence signal detected above 650 nm is disappearingly small) and a second wavelength region (which does not intersect with the first wavelength region), in which spectrally there lies the additional illumination light from the light source (red light, wavelengths greater than 700 nm). The auto fluorescence signal is led to a first camera whose signals are led to a first color input of a monitor and the remitted red light is led to a second camera whose signals are led to a second colour input of the monitor (e.g. red).
In U.S. Pat. No. 5,590,660, the signal supplied to the second colour channel of the monitor is independent of the degree of tissue atypia (with the advantages with respect to the colour differentiation described in detail above) since the detection region of the second camera which delivers signals to this second monitor input lies outside the wavelength region of the emitted tissue autofluorescence signals whose intensity in turn is dependent on the condition of the tissue. A signal derived from the auto fluorescence and dependent on the tissue condition may not be superimposed on the second signal which is constant with respect to the tissue condition. Accordingly, the second channel may with a suitable metering of the additional illumination light be used as a colour reference with respect to the tissue condition dependent fluctuations of the signals fed into the first channel.
A disadvantage of U.S. Pat. No. 5,590,660 is that the cameras to be used or their sensors may not be part of a conventional 3-chip camera since the first detection region comprises the wavelength region of the whole autofluorescence light which consists of green light but also of red light, whilst the second detection region does not intersect with this first region and accordingly may only lie in the long-wave red spectral region. A conventional 3-chip camera however separates red from green already in a considerably more shortwave region. Thus if a white light diagnosis is carried out with a 3-chip camera then a further conventional colour camera is necessary. The device of U.S. Pat. No. 5,590,660 is necessarily complicated, awkward to use, and expensive. The fact that the wavelength region led to the first camera is so wide or reaches so far into the red spectral region is disadvantageous in that tissue differentiation between the fluorescence curves for the different tissue conditions towards the longwave region, in particular where the yellow and red spectral region approach one another, becomes more and more washed.
Furthermore, U.S. Pat. No. 5,772,580 discloses a diagnosis system which does away completely with the detection of red light with the assessment of tissue, i.e. does away with the red fluorescence as well as additional red light provided by the light source and remitted at the tissue. The transmission region of the sensor applied here lies between 480 nm and 600 nm. Although an increased sensitivity for pre-malignant or early-malignant lesions is achieved, there arise the above mentioned disadvantages entailed when one makes do without the red reference such as the reduced specificity by way of an increased false-positive rate. Although a white light diagnosis is possible, a second camera is necessary. Furthermore making do without the detection of red light (fluorescence as well as red light remitted at the tissue) means a loss of brightness. Thus the system therefore also uses large, heavy and awkward image intensifiers in order to achieve a sufficiently bright picture.
Other diagnosis devices detect blue light instead of additional red light emitted by the light source and remitted at the tissue with the aim of an improved light contrasting of the tissue in the diagnosis mode of the autofluorescence. According to this device, a smaller part share of the blue light made available by the light source for fluorescence excitation which is not absorbed by the tissue but is remitted at the tissue is detected by the camera and not, as with the other known systems, completely blocked (for example by optical filters). At the same time the blue part share reaching the camera by way of optical filter technology is specified such that healthy tissue appears green to the observer and diseased tissue appears bluish. The assessment of the degree of disease of the tissue is effected thus essentially by the assessment of the different green-blue part shares. This method is disadvantageous because, in contrast to red light, blue light has a lower tissue penetration depth. The directly reflected part share of the blue light remitted by the tissue is larger than with red light. Accordingly, the homogeneously scattered back part share of the blue light is less than with red light. Since the tissue fluorescence light however is emitted relatively homogeneously almost independently of the incidence angle of the excitation light (isotrope), the colour impression at the observer arising from the sum of the fluorescence and the blue light remitted at the tissue is heavily dependent on the angle of incidence of the excitation and illumination light, and specifically much greater than with the detection of fluorescence light and of red light remitted by the tissue. The tissue assessment is thus dependent on the incidence angle of the illumination and excitation light which of course is not at all desirable.